Fuchs’ uveitis syndrome: a 20-year experience in 466 patients

Fuchs Uveitis Syndrome (FUS), also known as Fuchs Heterochromic Iridocyclitis, is a chronic form of uveitis characterized by mild inflammation primarily affecting one eye. This study aimed to investigate the clinical and epidemiological features of FUS in an Iranian population. A retrospective analysis was conducted on 466 patients diagnosed with FUS at an ophthalmology center affiliated with Isfahan University of Medical Sciences between 2003 and 2021. The Kimura et al. criteria were used for FUS diagnosis. Demographic data, clinical characteristics, misdiagnosed cases, concurrent diseases, and associated ocular findings were analyzed. The study included 507 eyes of 466 FUS patients, with a mean age of 34.01 ± 11.25 years. Iris atrophy, keratic precipitates, and vitritis were common clinical findings. Heterochromia was an infrequent feature. Initial misdiagnosis occurred in 13 patients, with pars planitis being the most common incorrect diagnosis. Toxoplasmosis and multiple sclerosis were common concurrent diseases. Pediatric FUS cases were noted, possibly attributed to early-onset manifestations. Differences in clinical characteristics were observed when compared to other populations. This study provides insights into the clinical and epidemiological aspects of FUS in an Iranian population. Variations in clinical features, misdiagnosis patterns, and concurrent diseases were noted. Attention to specific clinical parameters can aid in accurate FUS diagnosis. Understanding these differences contributes to a better understanding of FUS presentation and its relationship with other diseases.


Statistical methods
Frequency distribution tables were used to report categorical variables, and numerical variables were described with median and range.The relationship between each categorical variable and age group and sex was assessed by Chi-square test or Fisher exact test.Statistical analysis was performed with SPSS-18 software at a 95% confidence level.

Ethics approval
The protocol for this study was approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran (Code: IR.MUI.MED.REC.1398.72).
Eighteen eyes of 13 patients had initially misdiagnosed as other uveitis.The initial diagnosis of these patients before follow up were pars planitis (PP) (8/13), toxoplasmosis (2/13), posterior scleritis (1/13), Posner-Schlossmann syndrome (1/13), and undiagnosed case (1/13).Table 1 presents a comparison of demographic and clinical characteristics between patients/eyes correctly diagnosed as FUS and patients/eyes initially misdiagnosed as other uveitis.Bilateral involvement was more common in the group with an initially wrong diagnosis (P = 0.005).Iris atrophy and cataract in the misdiagnosed group had a lower rate compared to the corrected diagnosis group (P < 0.001 and P = 0.003, respectively).In addition, patients in the misdiagnosed group had a higher rate of glaucoma (P = 0.02) (Table 1).
Comparison of clinical findings between pediatrics/adults and male/female are summarized in Table 2. Iris atrophy was more common in adult patients (98.3% in adults versus.92% in pediatrics; P = 0.08).
Eight patients with FUS were misdiagnosed as having Behcet disease (BD) and were on immunosuppressive therapy when referred to our referral center.Table 3 presents concurrent findings and diseases in FUS patients.The most common concurrent diseases were toxoplasmosis (30 eyes of 18 patients) and multiple sclerosis (6 patients).The most common concurrent ocular findings were epiretinal membrane (15 patients), amblyopia (12 patients), and retinal detachment (RD) (5 patients) (Table 3).

Discussion
The result of our study identified several differences between the FUS in our population compared to others.Iris heterochromia was an uncommon clinical feature and PP was the most common causes of mistaken diagnosis in our study.The most common concurrent diseases in our study were toxoplasmosis and multiple sclerosis (MS).Differences in the clinico-epidemiological pattern of FUS can be attributed to geographic, ethnicity, and genetic/epigenetic factors.These findings can provide new insights into the clinical and epidemiological aspects of FUS.
Although there are some differences between the results of our study and previous studies, major demographic data and most clinical characteristic of FUS were similar to other studies 14,15,[21][22][23] .Consistent with the previous study in another Iranian population 18 , in our study iris heterochromia was an uncommon clinical feature.In contrast, studies from European countries showed that heterochromia is a more common finding in FUS [24][25][26] .A possible explanation for this contrast can be attributed to oculocutaneous phenotype.In fair phenotype due to pigmentary dilution of iris, the pigmentary changes related to the FUS may be more apparent.
FUS varies widely in differential diagnosis and can be considered as a great imitator in differential diagnosis of uveitis.FUS may be misdiagnosed due to its similarity to other inflammatory conditions or uveitis.FUS should be considered in all patients with uveitis, especially in patients with a history of uncertain clinical criteria for other differential diagnoses.Similar to previous studies, PP was the most common cause of misdiagnosis in our study 18,27,28 .Existence of iris changes, bilateral involvement, cataract, and glaucoma were four factors that differed between accurate and mistaken diagnoses of FUS in our study.In challenging cases, attention to changes in iris pigment, unilateral involvement, and existence of cataract can be helpful parameter for true diagnosis of FUS.
In our study, there is a possible important linkage between FUS with Toxoplasmosis.Many authors have looked for a link between toxoplasmosis and FUS 29 .For example in the study of Toledo de Abreu et al. association of FUS with ocular toxoplasmosis was seen in 13 patients in FUS 30 .
It is unclear whether this relatively high co-incidence of FUS and these conditions are related to the high prevalence of toxoplasmosis in our area, up to 43% seroprevalence according to some reports 31 , or a direct association 32 .Although it cannot be excluded that in some patients with FUS, the observed Toxoplasmosis may represent a co-incidence of two diseases, there is some hypothesis for a potential association between Toxoplasmosis and FUS.
In addition, regarding a possible association between toxoplasmosis and FUS, six patients had FUS co-existing with MS.Regarding the high prevalence of MS in our area, Isfahan, Iran 33,34 , further investigation is necessary for the identification of possible association of MS and FUS and possible etiopathogenesis pathway or incidental co-occurrence.
The frequency of RD in FUS is not well defined.Five patients in our study had RD.Severe inflammation of the vitreous may lead to vitreous traction causing the tractional and rhegmatogenous retinal detachment 35 .
FUS is a great imitator and a wide range of differential diagnoses should be considered for accurate diagnosis.In our study 8 patients were referred to us with clinical impression of BD, while on exact ocular examination and re-checking of the clinical criteria, the primary diagnoses of BD were ruled out, and patients were considered as FUS.On the other hand, eight patients had diagnoses of FUS and with long-term follow-up, alternative diagnoses were confirmed.FUS is a disease of young adults and childhood FUS is a rare condition 17 .In our study, 25 patients had childhood FUS.On one hand, the relatively higher patient count can be ascribed to a selection bias stemming from the referral center's focus on uveitis.On the other hand, FUS might initiate during early childhood, yet its clinical manifestations might not manifest at the disease's outset.Consequently, diagnosis could potentially be postponed for several years 17 .
Although our study had some limitations including the retrospective nature of the study, current study, which included 507 eyes from 466 patients, can provide some references for the difference of FUS between Iranian subjects and others.Note that the number of cases in our study in comparison with others is considerable.

Conclusion
The current study demonstrated several differences between Iranian FUS patients and others, including clinical features, misdiagnosis patterns, and concurrent diseases.In challenging cases, attention to changes in iris pigment, unilateral involvement, and existence of cataract can be helpful parameter for the true diagnosis of FUS.

Table 1 .
Comparison of demographic and clinical characteristics between patients/eyes correctly diagnosed as FU and patients/eyes initially misdiagnosed as other uveitis.*P-value resulted from Mann-Whitney U test or Chi-squared (or Fisher exact test) for between groups comparisons.KP keratic precipitate.PCIOL posterior chamber intraocular lens, AC anterior chamber.